Related Experiment Video
Updated: Aug 5, 2026
Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Smart nanoplatform targeting the mitochondria-P-gp axis to overcome chemoresistance for synergistic bladder cancer
Zhihua Zeng1, Chao Hu1, Yihe Li1
1Department of Urology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330000, PR China.
Abstract:
Chemoresistance remains a major obstacle in bladder cancer therapy, driven by the interplay among P-glycoprotein (P-gp)-mediated drug efflux, mitochondrial metabolic reprogramming, and impaired apoptotic signaling. Here, we present a TME-responsive nanoplatform (DR@MPDA@M) composed of MPDA core shielded by manganese dioxide (MnO2) shell, enabling sequential co-delivery of doxorubicin and resveratrol for chemo-/chemodynamic/photothermal therapy. The MnO2 layer selectively degrades under the acidic and glutathione-rich TME, enabling controlled drug release while simultaneously generating Mn2+ that catalyze Fenton-like reactions to produce cytotoxic hydroxyl radicals (•OH). Notably, this design strategically targets the mitochondria-P-gp axis that resveratrol potently downregulates P-gp expression to suppress drug efflux, while the Mn2+-induced oxidative stress disrupts mitochondrial function, depleting intracellular ATP and inhibiting heat shock protein 90. The resultant energy crisis synergistically impairs P-gp-mediated efflux and sensitizes cancer cells to doxorubicin-induced apoptosis. Upon 808 nm laser irradiation, the MPDA core mediates photothermal conversion, further accelerating the Fenton-like reaction and potentiating chemotherapy. Both in vitro and in vivo bladder tumor models demonstrate that DR@MPDA@M achieves favourable tumor inhibition. This work provides a mitochondria-P-gp axis-targeted strategy that integrates chemo-/chemodynamic/photothermal therapy, offering a promising paradigm for overcoming chemoresistance in bladder cancer.
Insights
This study introduces a novel nanoplatform (DR@MPDA@M) that overcomes bladder cancer chemoresistance by targeting the mitochondria-P-glycoprotein (P-gp) axis. It combines chemotherapy, chemodynamic therapy, and photothermal therapy for enhanced tumor inhibition.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Chemoresistance is a significant challenge in bladder cancer treatment.
- Key mechanisms include P-glycoprotein (P-gp) efflux, mitochondrial dysfunction, and apoptosis evasion.
- Targeting these pathways offers a strategy to improve therapeutic outcomes.
Purpose of the Study:
- To develop a TME-responsive nanoplatform for sequential drug delivery.
- To investigate a novel strategy targeting the mitochondria-P-gp axis to overcome chemoresistance.
- To evaluate the combined chemo-, chemodynamic-, and photothermal therapeutic efficacy of the nanoplatform.
Main Methods:
- A TME-responsive nanoplatform (DR@MPDA@M) was designed with a manganese dioxide (MnO2) shell for controlled release of doxorubicin and resveratrol.
- The nanoplatform utilizes Mn2+-catalyzed Fenton-like reactions for chemodynamic therapy and photothermal conversion upon laser irradiation.
- In vitro and in vivo bladder cancer models were used to assess tumor inhibition.
Main Results:
- The nanoplatform demonstrated selective degradation in the tumor microenvironment (TME), releasing drugs and generating cytotoxic hydroxyl radicals.
- Resveratrol downregulated P-gp expression, while Mn2+-induced oxidative stress disrupted mitochondrial function, creating an energy crisis.
- The combined therapeutic approach synergistically enhanced doxorubicin efficacy and induced cancer cell apoptosis, leading to significant tumor inhibition in both in vitro and in vivo models.
Conclusions:
- The DR@MPDA@M nanoplatform effectively targets the mitochondria-P-gp axis, integrating multiple therapeutic modalities.
- This approach shows promise in overcoming chemoresistance in bladder cancer.
- The study presents a viable strategy for enhancing bladder cancer therapy through synergistic multi-modal treatment.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...